Skip to main content

Integration of Target-Based Agents in Current Protocols of Breast Cancer Therapy

  • Chapter
  • First Online:
Breast Cancer in the Post-Genomic Era

Summary

Breast cancer is a heterogeneous disease sustained by the dysregulation of numerous molecular pathways, such as cell cycle progression, angiogenesis, and apoptosis. Recent progress in molecular technology has allowed better characterization of the transformed phenotype, identifying molecular features that distinguish tumor from normal tissue and represent rational targets for more selective therapeutic approaches. In this chapter, we focus on the molecular target-based agents in the most advanced state of clinical development in breast cancer. Trastuzumab, a monoclonal antibody with high specificity for the HER2 protein, is the first targeted agent approved for the treatment of metastatic and early breast cancer. Bevacizumab, a monoclonal antibody directed against the VEGF-A ligand, with antiangiogenetic properties, and lapatinib, a dual tyrosine-kinase inhibitor of both EGFR and HER2, have been recently approved for use in the treatment of metastatic breast cancer. Several other compounds directed against different targets have also entered clinical evaluation. Key issues in the clinical development of targeted therapy include the proper selection of patients, the identification of the optimal combinations with conventional treatments, predictive markers of activity and toxicity, and the most appropriate therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000 The global picture. Eur J Cancer 2001;37:S4–S66.

    Article  PubMed  Google Scholar 

  2. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Critical Rev Oncol Hematol 1995;19:183–232.

    Article  CAS  Google Scholar 

  3. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–182.

    Article  CAS  PubMed  Google Scholar 

  4. Querrel N, Wafflart J, Borrichon F, et al. The prognostic value of c-erbB2 in primary breast carcinomas: a study of 942 cases. Breast Cancer Res Treat 1995;35:283–291.

    Article  Google Scholar 

  5. Pegram MD, Finn RS, Arzoo K, et al. The effect of her-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 1997;15:537–547.

    Article  CAS  PubMed  Google Scholar 

  6. Carlomagno C, Perrone F, Gallo C, et al. c-ErbB2 overexpression decreases the benefit of adjuvant tamoxifen in early breast cancer without axillary lymph node metastases. J Clin Oncol 1996;14:2702–2708.

    CAS  PubMed  Google Scholar 

  7. Cobleigh M, Vogel C, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639–2648.

    CAS  PubMed  Google Scholar 

  8. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Semin Oncol 1999;26:78–83.

    CAS  PubMed  Google Scholar 

  9. Vogel C, Cobleigh M, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719–726.

    Article  CAS  PubMed  Google Scholar 

  10. Slamon D, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.

    Article  CAS  PubMed  Google Scholar 

  11. Osoba D, Slamon DJ, Burhmore M, et al. 2002 Effects on quality of life of combined trastuzumab and chemotherapy in women with metastatic breast cancer. J Clin Oncol 2002;20:3106–3113.

    Article  CAS  PubMed  Google Scholar 

  12. Fountzilas G, Tsavdaridis D, Kalogera-Fountzila Aet al, et al. Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer A Hellenic Cooperative Oncology Group phase II study. Ann Oncol 2001;12:1545–1551.

    Article  CAS  PubMed  Google Scholar 

  13. Seidman AD, Fornire MN, Esteva FJ, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001;19:2587–2525.

    CAS  PubMed  Google Scholar 

  14. Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol 2003;21:3965–3971.

    Article  CAS  PubMed  Google Scholar 

  15. Gori S, Colozza M, Mosconi AM, et al. Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2- overexpressing metastatic breast cancer. Br J Cancer 2004;90:36–40.

    Article  CAS  PubMed  Google Scholar 

  16. Gasparini G, Gion G, Mariani L, et al. Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer. Breast Cancer Res Treat 2007;101:355–365.

    Article  CAS  PubMed  Google Scholar 

  17. Esteva FJ, Valero V, Booser D, et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2–overexpressing metastatic breast cancer. J Clin Oncol 2002;20:1800–1808.

    Article  CAS  PubMed  Google Scholar 

  18. Tedesco KL, Thor AD, Johnson DH, et al. Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization–positive metastatic breast cancer: a multi-institutional phase II trial. J Clin Oncol 2004;22:1071–1077.

    Article  CAS  PubMed  Google Scholar 

  19. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer administered as first-line treatment: the M77001 Study Group. J Clin Oncol 2005;23:4265–4274.

    Article  CAS  PubMed  Google Scholar 

  20. Burstein HJ, Kuter I, Campos SMet al, et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 2001;19:2722–2730.

    CAS  PubMed  Google Scholar 

  21. Jahanezeb M, Joanne E, Mortimer JE, et al. Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2+ metastatic breast cancer. Oncologist 2002;7:410–417.

    Article  Google Scholar 

  22. Burstein HJ, Harris LN, Marcom PK, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003;21:2889–2895.

    Article  CAS  PubMed  Google Scholar 

  23. Chan A, Martin M, Untch M, et al. Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial. Br J Cancer 2006;95:788–793.

    Article  CAS  PubMed  Google Scholar 

  24. Papaldo P, Fabi A, Ferretti G, et al. A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease. Ann Oncol 2006;17:630–636.

    Article  CAS  PubMed  Google Scholar 

  25. De Maio E, Pacilio C, Gravina A, et al. Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer A single-centre phase 2 trial. BMC Cancer 2007;7:50.

    Article  PubMed  Google Scholar 

  26. Yamamoto D, Iwase S, Kitamura K, et al. A phase II study of trastuzumab and capecitabine for patients with HER2-overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial. Cancer Chemother Pharmacol 2008;61:509–514.

    Article  CAS  PubMed  Google Scholar 

  27. Schaller G, Fuchs I, Gonsch T, et al. Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes. J Clin Oncol 2007;25:3246–3250.

    Article  CAS  PubMed  Google Scholar 

  28. Pegram MD, Lipton A, Hayes DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998;16:2659–2671.

    CAS  PubMed  Google Scholar 

  29. O’Shaughnessy JA, Vukelja S, Marsland T, et al. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer. Clin Breast Cancer 2004;5:142–147.

    Article  PubMed  Google Scholar 

  30. Burris H, Yardley D, Jones Set al, Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer. J Clin Oncol 2004;22:1621–1629.

    Article  CAS  PubMed  Google Scholar 

  31. Pegram MD, Pienkowski T, Northfelt DW, et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 2004;96:759–769.

    Article  CAS  PubMed  Google Scholar 

  32. Perez EA, Suman VJ, Rowland KM, et al. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer 2005;6:425–432.

    Article  CAS  PubMed  Google Scholar 

  33. Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2–overexpressing metastatic breast cancer. J Clin Oncol 2006;24:2786–2792.

    Article  CAS  PubMed  Google Scholar 

  34. Morabito A, Longo R, Gattuso D, et al. Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpressing metastatic breast cancer. Oncol Rep 2006;16:393–398.

    CAS  PubMed  Google Scholar 

  35. Fujimoto-Ouchi K, Sekiguchi F, Kazushige M. Preclinical study of continuous administration of trastuzumab as combination therapy after disease progression with trastuzumab monotherapy. Proc Am Assoc Cancer Res 2005;46:5062a.

    Google Scholar 

  36. Fountzilas G, Razis E, Tsavdaridis D, et al. Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: A retrospective analysis of 80 cases by the Hellenic Cooperative Oncology Group. Clin Breast Cancer 2003;4:120–125.

    Article  CAS  PubMed  Google Scholar 

  37. Gelmon KA, Mackey J, Verma S, et al. Use of trastuzumab beyond disease progression: Observations from a retrospective review of case histories. Clin Breast Cancer 2004;5:52–58; discussion 59–62.

    Google Scholar 

  38. Tripathy D, Slamon DJ, Cobleigh M, et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 2004;22:1063–1070.

    Article  CAS  PubMed  Google Scholar 

  39. Montemurro F, Donadio M, Clavarezza M, et al. Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy. The Oncologist 2006;11:318–324.

    Article  CAS  PubMed  Google Scholar 

  40. Bartsch R, Wenzel C, Hussian D, Analysis of trastuzumab and chemotherapy in advanced breast cancer after the failure of at least one earlier combination: An observational study. BMC Cancer 2006;6:63.

    Article  PubMed  Google Scholar 

  41. Bartsch R, Wenzel C, Altorjai G, et al. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol 2007;25:3853–3858.

    Article  CAS  PubMed  Google Scholar 

  42. Bartsch R, Wenzel C, Gampenrieder SP, et al. Trastuzumab and gemcitabine as salvage therapy in heavily pre-treated patients with metastatic breast cancer. Cancer Chemother Pharmacol 2008 Feb 7 [Epub ahead of print].

    Google Scholar 

  43. Jones A. Combining trastuzumab (Herceptin®) with hormonal therapy in breast cancer: what can be expected and why? Ann Oncol 2003;14:1697–1704.

    Article  CAS  PubMed  Google Scholar 

  44. Mackey JR, Kaufman B, Clemens M, et al Trastuzumab prolongs progression-free survival in hormone-dependent and HER2-positive metastatic breast cancer. Breast Cancer Res Treat 2006;100 (suppl 1):S5. abst 3.

    Google Scholar 

  45. Marcom PK, Isaacs C, Harris L, et al. The combination of letrozole and trastuzumab as first- or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. Breast Cancer Res Treat 2007;102:43–49.

    Article  CAS  PubMed  Google Scholar 

  46. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–1672.

    Article  CAS  PubMed  Google Scholar 

  47. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684.

    Article  CAS  PubMed  Google Scholar 

  48. Slamon D, Eiermann W, Robert N, et al. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC薔T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC薔TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. 29th Annual San Antonio Breast Cancer Symposium Proc; December 14–17, 2006; San Antonio, TX. abst 52.

    Google Scholar 

  49. Joensuu H, Kellokumpu-Lehtinen P-L, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809–820.

    Article  CAS  PubMed  Google Scholar 

  50. Coon JS, Marcus E, Gupta-Burt S, et al. Amplification and overexpression of topoisomerase II alpha predict response to anthracycline-based therapy in locally advanced breast cancer. Clin Cancer Res 2002;8:1061–1067.

    CAS  PubMed  Google Scholar 

  51. Nahta R, Hung MC, Esteva1 FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004;64:2343–2346.

    Article  CAS  PubMed  Google Scholar 

  52. Baselga J, Cameron D, Miles D, et al. Objective response rate in a phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T. J Clin Oncol 2007 ASCO Annual Meeting Proceedings; 25(18S):abst 1004.

    Google Scholar 

  53. Rusnak DW, Affleck K, Cockerill SG, et al. The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res 2001;61:7196–7203.

    CAS  PubMed  Google Scholar 

  54. Spector NL, Xia W, Burris H III, et al. Study of the Biologic Effects of Lapatinib, a Reversible Inhibitor of ErbB1 and ErbB2 Tyrosine Kinases, on Tumor Growth and Survival Pathways in Patients With Advanced Malignancies. J Clin Oncol 2005;23:2502–2512.

    Article  CAS  PubMed  Google Scholar 

  55. Burris HA III, Hurwitz HI, Dees EC, et al. Phase I Safety, Pharmacokinetics, and Clinical Activity Study of Lapatinib (GW572016), a Reversible Dual Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinases, in Heavily Pretreated Patients With Metastatic Carcinomas. J Clin Oncol 2005;23:5305–5313.

    Article  CAS  PubMed  Google Scholar 

  56. Blackwell KL, Burstein H, Pegram M, et al. Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab refractory metastatic breast cancer. J Clin Oncol 2005;23(16 suppl).

    Google Scholar 

  57. Burstein H, Storniolo AM, Franco S, et al. A phase II of lapatinib monotherapy in chemotherapy refractory HER2-positive and HER2-negative advanced or metastatic breast cancer. Ann Oncol 2008 in press.

    Google Scholar 

  58. Chu QS, Schwartz G, de Bono J, et al. Phase I and pharmacokinetic study of lapatinib in combination with capecitabine in patients with advanced solid malignancies. J Clin Oncol 2007;25:3753–3758.

    Article  CAS  PubMed  Google Scholar 

  59. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733–2743.

    Article  CAS  PubMed  Google Scholar 

  60. Di Leo A, Gomez H, Aziz Z, et al. Lapatinib with paclitaxel compared to paclitaxel as first-line treatment for patients with metastatic breast cancer: a phase III randomized, double-blind study of 580 patients. J Clin Oncol 2007;25:abst 1011.

    Google Scholar 

  61. Spector NL, Blackwell K, Hurley J, et al. EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): clinical activity and biologic predictors of response. J Clin Oncol 2006;24(18 suppl).

    Google Scholar 

  62. Xia W, Bacus S, Hegde P, et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. PNAS 2006;103:7795–7800.

    Article  CAS  PubMed  Google Scholar 

  63. Chu I, Blackwell K, Chen S, et al. The dual ErbB1/ErbB2 inhibitor, lapatinib, cooperates with tamoxifen to inhibit both cell proliferation and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res 2005;65:18–25.

    CAS  PubMed  Google Scholar 

  64. Chu Q, Goldstein L, Murray N, et al. A phase I, open-label study of the safety, tolerability and pharmacokinetics of lapatinib (GW572016) in combination with letrozole in cancer patients. J Clin Oncol 2005;23:abst 3001.

    Google Scholar 

  65. Perez EA, Byrne JA, Hammond IW, et al. Results of an analysis of cardiac function in 2812 patients treated with lapatinib. Proc Am Soc Clin Oncol 2006;24:abst 583.

    Google Scholar 

  66. Storniolo AM, Koehler M, Preston A, et al. Cardiac safety in patients with metastatic breast cancer treated with lapatinib and trastuzumab. Proc Am Soc Clin Oncol 2007;25:abst 514.

    Google Scholar 

  67. Hanahan D, Folkman J. patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–364.

    Article  CAS  PubMed  Google Scholar 

  68. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 1993;362:841–844.

    Article  CAS  PubMed  Google Scholar 

  69. Fox SB, Gasparini G, Harris AL. Angiogenesis: pathological, prognostic and growth factor pathways and their link to trial design and anticancer drugs. Lancet Oncol 2001;2:278–289.

    Article  CAS  PubMed  Google Scholar 

  70. Toi M, Matsumoto T, Bando H, Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol 2001;2:667–673.

    Article  CAS  PubMed  Google Scholar 

  71. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001;19:843–850.

    CAS  PubMed  Google Scholar 

  72. Margolin K, Gordon MS, Holmgren E, et al. Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol 2001;19:851–856.

    CAS  PubMed  Google Scholar 

  73. Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 2003;30:117–124.

    Article  CAS  PubMed  Google Scholar 

  74. Burstein HJ, Parker LM, Savoie J, et al. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Cancer Res Treat 2002;79: (S115)abst 446.

    Google Scholar 

  75. Ramaswamy B, Elias AD, Kelbick NT, et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–3129.

    Article  CAS  PubMed  Google Scholar 

  76. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–799.

    Article  CAS  PubMed  Google Scholar 

  77. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666–2676.

    Article  CAS  PubMed  Google Scholar 

  78. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006;12:895–904.

    Article  CAS  PubMed  Google Scholar 

  79. Lyons JA, Silverman P, Remick S, et al. Toxicity results and early outcome data on a randomized phase II study of docetaxel ± bevacizumab for locally advanced, unresectable breast cancer. J Clin Oncol 2006, ASCO Annual Meeting Proceedings; 24 (18S): abst 3049.

    Google Scholar 

  80. Wedam SB, Law JA, Yang SX, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 2006;24:769–777.

    Article  CAS  PubMed  Google Scholar 

  81. Burstein HJ, Elias AD, Rugo HS, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008;26:1810–1816.

    Article  CAS  PubMed  Google Scholar 

  82. Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. The Oncologist 2006;11:753–764.

    Article  CAS  PubMed  Google Scholar 

  83. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004;4:335–348.

    Article  CAS  PubMed  Google Scholar 

  84. Yu K, Toral-Barza L, Discafani C, et al: mTOR, a novel target in breast cancer: The effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 2001;8:249–258.

    Article  PubMed  Google Scholar 

  85. DeGraffenried LA, Friedrichs WE, Russel DH, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clin Cancer Res 2004;10:8059–8067.

    Article  CAS  PubMed  Google Scholar 

  86. Del Bufalo D, Ciuffreda L, Trisciuoglio D, et al. Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 2006;66:5549–5554.

    Article  CAS  PubMed  Google Scholar 

  87. Raymond E, Alexandre J, Faivre S, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. Clin Oncol 2004;22:2336–2347.

    Article  CAS  Google Scholar 

  88. Peralba JM, deGraffenried L, Friedrichs W, et al. Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 2003;9:2887–2892.

    CAS  PubMed  Google Scholar 

  89. Chan S, Scheulen ME, Johnston S, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005;23:5314–5322.

    Article  CAS  PubMed  Google Scholar 

  90. Carpenter JT, Roché H, Campone M, et al. Randomized 3-arm, phase 2 study of temsirolimus (CCI-779) in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer J Clin Oncol 2005 ASCO Annual Meeting Proceedings; 23 (16S): abst 564.

    Google Scholar 

  91. Chow LWC, Sun Y, Jassem J, et al. Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. SABCS 2006 Proceedings; abst 6091.

    Google Scholar 

  92. Beuvink I, O’Reilly T, Zumstein S, et al: Antitumor activity of RAD001, an orally active rapamycin derivative. Proc Am Assoc Cancer Res 2001; 42:366 (suppl, abstr 1972).

    Google Scholar 

  93. Lu CH, Wyszomierski SL, Tseng LM, et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res 2007;13:5883–5888.

    Article  CAS  PubMed  Google Scholar 

  94. Bianco R, Garofalo S, Rosa R, et al. Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 2008;98:923–30.

    Article  CAS  PubMed  Google Scholar 

  95. Boulay A, Rudloff J, Ye J, et al. Dual inhibition of mTOR pathway and estrogen signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 2005;11:5319–5328.

    Article  CAS  PubMed  Google Scholar 

  96. Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008;26:1603–1610.

    Article  CAS  PubMed  Google Scholar 

  97. Macaskill EJ, Bartlett JMS, White S, et al. The mammalian target of rapamycin inhibitor RAD001 (everolimus) in postmenopausal women with early breast cancer: results of a phase II pre-operative trial. SABCS 2006 Proceedings; abst 6092.

    Google Scholar 

  98. Baselga J, Semiglazov V, van Dam P, et al. Phase II double-blind randomized trial of daily oral RAD001 (everolimus) plus letrozole (LET) or placebo (P) plus LET as neoadjuvant therapy for ER+ breast cancer. SABCS 2007 Proceedings; abst 2066.

    Google Scholar 

  99. Gardner H, Bandaru R, Barrett C, et al. Biomarker analysis of a phase II double-blind randomized trial of daily oral RAD001 (everolimus) plus letrozole or placebo plus letrozole as neoadjuvant therapy for patients with estrogen receptor positive breast cancer. SABCS 2007 Proceedings; abst 4006.

    Google Scholar 

  100. Morabito A, Di Maio M, De Maio E, et al. Methodology of clinical trials with new molecular-targeted agents: where do we stand? Ann Oncol 2006;17(suppl 7):vii128–vii131.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Humana Press, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Piccirillo, M.C. et al. (2009). Integration of Target-Based Agents in Current Protocols of Breast Cancer Therapy. In: Giordano, A., Normanno, N. (eds) Breast Cancer in the Post-Genomic Era. Current Clinical Oncology. Humana Press. https://doi.org/10.1007/978-1-60327-945-1_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-945-1_12

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-944-4

  • Online ISBN: 978-1-60327-945-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics